Ample data over the last 20 years strongly support an important role of the epidermal growth factor receptor (EGFR) in head and neck squamous cell carcinomas (HNSCC). Several pharmaceutical companies have developed EGFR inhibitors for the treatment of this disease. While there have been some early success of these drugs in clinical trials, the response is not as dramatic as one would like. Thus, additional molecular predictors for response are urgently needed. Recent data suggested that there is potential cross talk between EGFR and Ron. We also discovered that overexpressing Ron not only transactivates EGFR, but also modulates its signaling such that the EGFR inhibitors can no longer exert their maximal effects. In addition, we found that Ron is expressed at high levels in some primary HNSCCs and that Ron+ HNSCCs are more likely to have phosphorylated EGFR. Based on these early results, we formulate the following hypothesis: Ron functionally interacts with EGFR to confer a more aggressive disease phenotype in HNSCC. We propose to test our hypothesis with two specific aims: (1) We will determine the prevalence of Ron in primary HNSCCs and correlate its expression with prognosis. (2) We will investigate if squamous cell carcinoma cell lines that express high level of both Ron and EGFR are more refractory to the action of EGFR inhibitors. In aim 1, we will determine Ron and EGFR expression profiles in primary HNSCCs using three molecular methods;then, we will perform correlation analysis to determine if high Ron expression is indicative of more aggressive disease features and poor survival. In aim 2, we will perform cell biology and biochemical analyses to further understand the functional interaction of Ron with EGFR. We will test if such interaction modulates EGFR in such a way that EGFR inhibitors can no longer inhibit its signaling and exert their maximal effects. Our application has the following potential impact. (1) This project may identify Ron as a potential therapeutic target fo HNSCC;(2) Ron may also be a candidate prognostic biomarker for HNSCC. PUBLIC HEALTH RELEVANCE: We propose to understand the interaction between two cancer proteins, EGFR and Ron. The experiments not only address a potential reason why some EGFR inhibitors have not produced dramatic results;they will examine the prognostic value of a new molecular marker, Ron, for head and neck cancers.